SMYD3 regulates gastric cancer progression and macrophage polarization through EZH2 methylation.

SET and MYND domain-containing protein 3 (SMYD3), a known histone methyltransferase, was reported to regulate cancer pathogenesis. However, its role in gastric development and progression remains unclear. EZH2 methylation had been associated with cancer metastasis, but the EZH2 methylation status in gastric cancer (GC) is unknown. Here, we report that EZH2 K421 methylation was responsible for gastric cancer cell soft agar colony formation, in vivo metastasis, and macrophage polarization. Mechanically, we identified SMYD3 as the methyltransferase of EZH2 at K421 residue which accelerates EZH2 Ubiquitin proteasome degradation. Cell harboring non-methylated EZH2 mutants promotes gastric cancer cell metastasis. Taken together, our results showed that SMYD3-EZH2 axis restricts gastric cancer metastasis via integrating epigenetic signaling.

HOXC13-AS promotes breast cancer cell growth through regulating miR-497-5p/PTEN axis.

Dysregulated long noncoding RNAs (lncRNAs) remains to be explored in tumorigenesis. LncRNA HOXC13 antisense RNA (HOXC13-AS) has been found as an oncogene in many cancers; however, the role of HOXC13-AS in breast cancer still elusive. In this study, the HOXC13-AS levels and its role in cell proliferation was first measured by real-time quantitative polymerase chain reaction, Cell Counting Kit-8 assay, and colony formation assay. It showed that HOXC13-AS was increased in breast cancer tissues compared with the adjacent normal tissues and upregulated HOXC13-AS promoted the growth of breast cancer cells. Then, we found that the miR-497-5p levels were downregulated in cancer tissues compared with the adjacent tissues and miR-497-5p suppressed breast cancer cell proliferation. Further study showed that HOXC13-AS could function as a "sponge" for miR-497-5p then suppress miR-497-5p expression. Moreover, we next identified that Phosphatase and Tensin homolog (PTEN) is the target of miR-497-5p. Overexpression of miR-497-5p by chemical mimics decreased the expression of PTEN, while downregulation of miR-497-5p by HOXC13-AS rescued the expression of PTEN. Finally, we showed that HOXC13-AS promoted the proliferation of breast cancer cells and tumor growth through miR-497-5p/PTEN axis in vitro and in vivo. Hence, we conclude that HOXC13-AS, which is significantly upregulated in breast cancers, promoted cell proliferation through the suppressed miR-497-5p and further upregulated PTEN.

LncRNA HOTTIP mediated DKK1 downregulation confers metastasis and invasion in colorectal cancer cells.

Recent studies highlight long non-coding RNAs (lncRNAs) as key regulators of cancer biology that contribute to carcinogenesis. The lncRNA HOXA transcript at the distal tip (HOTTIP) is involved in the development of several cancers. Previous studies demonstrated that HOTTIP could promote colorectal cancer (CRC) cell proliferation via silencing of p21 expression. However, the potential role of HOTTIP in CRC metastasis has not yet been discussed. Here, we found that HOTTIP level was significantly higher in CRC than in corresponding adjacent normal tissues, and patients with a larger tumor size, advanced pathological stage, or distant metastasis had higher HOTTIP expression. Moreover, silencing HOTTIP expression by siRNA or shRNA could inhibit CRC cell migration and invasion in vitro and in vivo, whereas HOTTIP overexpression promoted cell metastasis, as documented in the SW480 cell lines. Mechanistic analyses indicated that HOTTIP regulates CRC cell metastasis partly through the downregulation of tumor suppressor DKK1 expression. Collectively, our results suggest that tumor expression of lncRNA HOTTIP plays an important role in CRC metastasis. HOTTIP may serve as a candidate biomarker in this disease.

Nurr1 promotes intestinal regeneration after ischemia/reperfusion injury by inhibiting the expression of p21 (Waf1/Cip1).

Intestinal ischemia/reperfusion (I/R) injury is a potentially life-threatening condition that can cause injuries to remote organs at the end stage. The damage caused by intestinal I/R insult induces changes in the barrier functions of the intestine, and the intrinsic mechanism of regeneration is often insufficient to restore barrier functions, as indicated by the high mortality rate of patients experiencing intestinal I/R injury. However, little is known about the mechanisms of intestinal regeneration after I/R injury. Here, we reported that nuclear receptor-related protein 1 (Nurr1), a nuclear orphan receptor, was induced during intestinal regeneration after I/R. Our findings showed that Nurr1 expression was consistent with the expression of Ki-67 and phosphorylated histone H3 (pH 3) in the intestine after I/R injury. Nurr1 knockdown led to G1-phase arrest mediated by p21 (Waf1/Cip1) activation, but Nurr1 overexpression reduced the proportion of IEC-6 cells in G1 phase as a result of p21 inhibition in a p53-independent manner. Using chromatin immunoprecipitation assays, luciferase assays, and mutational analysis, we demonstrated that Nurr1 directly inhibited the transcription of p21. These results define a novel Nurr1/p21 pathway that is involved in intestinal regeneration after I/R injury. These findings provide novel molecular insights into the pathogenesis of intestinal regeneration after I/R and possibly support the development of new potential therapies for intestinal I/R injury. KEY MESSAGE: Nurr1 was induced during intestinal regeneration after I/R injury. Nurr1 promoted proliferation of intestinal epithelial cells after H/R injury. Nurr1 inhibited p21 expression in a p53-independent manner. Nurr1 inhibited p21 gene transcription by binding to p21 promoter directly.